Pyrimidine 3-oxide compounds for inducing/stimulating hair growth and/or retarding hair loss

ABSTRACT

Hair growth-/hair loss-affecting cosmetic/therapeutic compositions contain an effective amount of at least one 2-amino-4-alkylaminopyrimidine 3-oxide having the structural formula (I):                    
     in which R 1  is an alkyl radical having from 5 to 20 carbon atoms, and Z is either a hydrogen atom or a radical —OR 2 , wherein R 2  is an alkyl radical having from 1 to 12 carbon atoms, or an acyl derivative or acid addition salt thereof.

CROSS-REFERENCE TO PRIORITY APPLICATION

This application claims priority under 35 U.S.C. §119 OF FR-98/09509,filed Jul. 24, 1998, assigned to the assignee hereof and herebyexpressly incorporated by reference.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to novel 2-amino-4-alkylaminopyrimidine3-oxide chemical compounds, to compositions comprised thereof and to theuse of such novel compounds/compositions as active principles forinducing and/or stimulating hair growth and/or for preventing hair loss.

2. Description of the Prior Art

In human subjects the growth and renewal of the hair are principallydetermined by the activity of the hair follicles. This activity iscyclic and essentially entails three phases, i.e., the anagenic phase,the catagenic phase and the telogenic phase.

The active anergenic phase, or growth phase, which lasts for severalyears and during which the hair elongates, is followed by a very shortand transient catagenic phase which lasts for a few weeks, and then arest or quiescent phase, designated the telogenic phase, which lasts fora few months.

At the end of the rest period, the hair falls out and another cyclebegins anew. The head of hair is thus under constant renewal, and out ofthe approximately 150,000 hairs on a head of hair, at any given instantapproximately 10% are at rest and will thus be replaced within a fewmonths.

However, different causes can lead to a considerable, temporary orpermanent, loss of hair. Alopecia is essentially due to a disruption inhair renewal which occasions, in a first stage, an acceleration of thefrequency of the cycles, at the expense of the quality of the hair andthen at the expense of its quantity. A gradual depletion of the head ofhair takes place by regression of the so-called “terminal” hairs at thedowny stage. Certain regions are preferentially affected, in particularthe temples or frontal bulbs in men, and in women, diffuse alopecia ofthe vertex is observed.

By the term “alopecia” are intended the entire family of afflictions ofthe hair follicle, the final consequence of which is the partial orgeneral permanent loss of the hair. In a large number of cases, earlyloss of the hair arises in genetically predisposed individuals andespecially affects men. This more particularly applies to androgeneticor androgenic or even androgeno-genetic alopecia.

Active substrates for suppressing or reducing alopecia, and inparticular for inducing or stimulating hair growth or reducing hairloss, have long been considered desiderata in the cosmetics andpharmaceutical industries.

In this respect, a large number of very diverse active compounds havealready been suggested for such purposes, for example,2,4-diamino-6-piperidinopyrimidine 3-oxide or “Minoxidil” described inU.S. Pat. Nos. 4,139,619 and 4,596,812, or the many derivatives thereof,such as those described, for example, in EP-0,353,123, EP-0,356,271,EP-0,408,442, EP-0,522,964, EP-0,420,707, EP-0,459,890 and EP-0,519,819.

Nonetheless, serious need continues to exist for yet other activeagents/species potentially more active and/or less toxic than thoseactive substrates to date characterizing the state of this art.

SUMMARY OF THE INVENTION

Accordingly, a major object of the present invention is the provision ofnovel 2-amino-4-alkylaminopyrimidine 3-oxide compounds having thestructural formula (I):

in which R₁ is an alkyl radical having from 5 to 20 carbon atoms, and Zis either a hydrogen atom or a radical —OR₂, wherein R₂ is an alkylradical having from 1 to 12 carbon atoms, as well as the acylderivatives or acid addition salts thereof.

The subject compounds are well suited as active principles for inducingand/or stimulating hair growth and/or preventing hair loss.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

More particularly according to the present invention, it is known tothis art that certain polyunsaturated fatty acids, in particular thosehaving 20 carbon atoms, such as arachidonic acid, dihomo-γ-linolenicacid and eicosapentaenoic acid, can be converted in vivo, under theinfluence of certain specific enzymes contained in living cells, inparticular epithelial cells, into certain yet other compounds ofeicosanoid type which are useful to the body.

Thus, it is known to this art that the enzymes designatedcyclooxygenated generate, from the different fatty acids indicatedabove, particularly from arachidonic acid, eicosanoids of prostaglandinand thromboxane type, and that the enzymes deemed lipoxygenases areresponsible for the formation of eicosanoids of leukotriene type andother hydroxylated acyclic acids containing 20 carbon atoms. Dependingon the nature of the enzyme with which it reacts first, the same givenpolyunsaturated fatty acid (or substrate) may be responsible for theformation of several different metabolites, namely, for example,prostaglandins and leukotrienes.

Cyclooxygenase activity can be defined as the enzymatic activity whichconverts certain polyunsaturated fatty acids into cyclized oxygenatedcompounds which are, indeed, highly unstable endoperoxides whichthereafter enter the subsequent metabolic pathways.

Prostaglandin-endoperoxide synthase, or cyclooxygenase (or PGHS, EC1.14.99.1), which is a haemoprotein, is an example of these enzymesexhibiting such activity. It is involved in one of the metabolicpathways of prostaglandins.

It too is known that the enzymatic transformations indicated above andthe various reaction products resulting therefrom exert an appreciableinfluence on the mechanisms of growth of body and/or head hair.

In this respect, it has now been shown that by promoting one or other ofthe two enzymatic pathways, cyclooxygenated or lipoxygenated, in skinand/or scalp cells, it is possible to substantially modify the growth ofbody and/or head hair. Compare EP-94/402,055, assigned to the assigneehereof.

Essentially, in the aforesaid patent application, promoting one of thepathways over the other is described, by the administration of acombination of compounds combining an inhibitor of one of the pathwayswith a stimulator of the other pathway.

Even more specifically, it has now been shown that the growth of bodyand/or head hair can be promoted and/or their loss can be controlled bypromoting the cyclooxygenase pathway, for example by activating PGHS andinhibiting the lipoxygenase pathway.

The involvement of these enzymes in several metabolic pathways and theconsequences which may ensue from deregulating their functioning aresuch that extensive research has been undertaken in order to developactive agents with the capacity either of increasing or of reducing theactivity of these enzymes.

Arachidonic acid metabolites, nitrogen monoxide andnitrogen-monoxide-donating compounds, stanozolol, glutathione-donatingcompounds, calcium ionophores, anthocyanosides, bioflavonoids, plateletactivating factors (PAF), pro-inflammatory cytokines agents andbacterial endotoxins are recognized, in particular, in the field ofcyclooxygenase activators.

Similarly, illustrative is 6-chloro-2,3-dihydroxy-1,4-naphthoquinone(CNDQ), which has the particular feature of being both a lipoxygenaseinhibitor and a cyclooxygenase stimulator (C. J. Bedord et al., TheJournal of Investigative Dermatology, 81:566-571 (1983)).

However, most of these species present the major drawback of having abroad functional spectrum, which entails that, in general, they have nogenuine specificity for cyclooxygenase. In this regard, the literatureon this subject reflects a wide variety of interpretation. Thesesubstrates can also be labile or their activity can depend on theirconcentration, which makes them difficult to administer.

The present inventors have thus sought to develop novel compounds whichhave activity at least on PGHS, and which would then be consideredcyclooxygenase activators.

After considerable research, it has now surprisingly and unexpectedlybeen determined that the 2-amino-4-alkylaminopyrimidine 3-oxides of theinvention have the property of activating PGHS.

Furthermore, the presence of an alkyl chain in the 4-position imparts tothese compounds improved lipophilic properties.

This reinforces the advantage of these compounds as active agents in thetreatment of hair loss.

Accordingly, this invention features novel compounds corresponding tothe structural formula (I):

in which R₁ is an alkyl group having from 5 to 20 carbon atoms, and Z iseither a hydrogen atom or a radical —OR₂, wherein R₂ is an alkyl grouphaving from 1 to 12 carbon atoms, as well as the acyl derivatives andacid addition salts thereof.

Consistent herewith, by the term “alkyl radical” is intended a linear orbranched acyclic radical originating from the removal of a hydrogen atomin a hydrocarbon molecule, such as, for example, a methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,octadecyl, nonadecyl or eicosadecyl radical.

In one preferred embodiment of the invention, R₁ is an alkyl radicalhaving from 6 to 12 carbon atoms, such as, for example, a hexyl, heptyl,octyl, nonyl, decyl, undecyl or dodecyl radicals.

In another preferred embodiment of the invention, R₂ is an alkyl radicalhaving from 2 to 6 carbon atoms, such as, for example, an ethyl, propyl,butyl, pentyl or hexyl radical.

Preferred compounds of the invention include:

2-amino-4-pentylaminopyrimidine 3-oxide;

2-amino-4-hexylaminopyrimidine 3-oxide;

2-amino-4-heptylaminopyrimidine 3-oxide;

2-amino-4-octylaminopyrimidine 3-oxide;

2-amino-4-nonylaminopyrimidine 3-oxide;

2-amino-4-decylaminopyrimidine 3-oxide;

2-amino-4-undecylaminopyrimidine 3-oxide;

2-amino-4-dodecylaminopyrimidine 3-oxide;

2-amino-4-tridecylaminopyrimidine 3-oxide;

2-amino-4-tetradecylaminopyrimidine 3-oxide;

2-amino-4-pentadecylaminopyrimidine 3-oxide;

2-amino-4-hexadecylaminopyrimidine 3-oxide;

2-amino-4-heptadecylaminopyrimidine 3-oxide;

2-amino-4-octadecylaminopyrimidine 3-oxide;

2-amino-4-nonadecylaminopyrimidine 3-oxide;

2-amino-4-eicosadecylaminopyrimidine 3-oxide;

2-amino-4-pentylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-hexylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-heptylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-octylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-nonylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-decylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-undecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-dodecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-tridecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-tetradecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-pentadecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-hexadecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-heptadecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-octadecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-nonadecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-eicosadecylamino-6-methoxypyrimidine 3-oxide;

2-amino-4-pentylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-hexylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-heptylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-octylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-nonylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-decylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-undecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-dodecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-tridecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-tetradecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-pentadecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-hexadecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-heptadecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-octadecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-nonadecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-eicosadecylamino-6-ethoxypyrimidine 3-oxide;

2-amino-4-pentylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-hexylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-heptylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-octylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-nonylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-decylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-undecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-dodecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-tridecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-tetradecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-pentadecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-hexadecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-heptadecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-octadecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-nonadecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-eicosadecylamino-6-propyloxypyrimidine 3-oxide;

2-amino-4-pentylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-hexylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-heptylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-nonylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-decylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-undecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-dodecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-tridecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-tetradecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-pentadecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-hexadecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-heptadecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-octadecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-nonadecylamino-6-butyloxypyrimidine 3-oxide;

2-amino-4-eicosadecylamino-6-butyloxypyrimidine 3-oxide; and

Even more preferred compounds according to the invention are:

2-amino-4-hexylaminopyrimidine 3-oxide;

2-amino-4-octylaminopyrimidine 3-oxide;

2-amino-4-dodecylaminopyrimidine 3-oxide;

2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide;

and yet even more preferred are

2-amino-4-dodecylaminopyrimidine 3-oxide; and

2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide.

This invention also features a process for preparing the2-amino-4-alkylaminopyrimidine 3-oxides of formula (I).

This process comprises reacting an aliphatic amine with2-amino-4,6-dichloropyrimidine in a solvent such as ethanol. Thecompound thus obtained, after purification, is then reacted with aurea/H₂O₂ complex and phthalic anhydride in a solvent such asisopropanol. After purification, the compound obtained is reacted in thepresence of potassium hydroxide and palladium-on-charcoal in a solventsuch as absolute ethanol, under a hydrogen pressure in order to providethe corresponding 2-amino-4-alkylaminopyrimidine 3-oxides.

The present invention also features a process for preparing the2-amino-4-alkylamino-6-alkyloxypyrimidine 3-oxides of formula (I).

This process comprises reacting an aliphatic amine with2-amino-4,6-dichloropyrimidine in a solvent such as ethanol. Thecompound thus obtained, after purification, is then reacted with aurea/H₂O₂ complex and phthalic anhydride in a solvent such asisopropanol. After purification, the compound obtained is reacted withan excess of sodium or potassium alkoxide to provide the corresponding2-amino-4-alkylamino-6-alkyl-oxypyrimidine 3-oxide.

Too, this invention features compositions which comprise at least onecompound of the 2-amino-4-alkylaminopyrimidine 3-oxides having thestructural formula (I).

It will of course be appreciated that the compositions according to theinvention can contain the compounds of formula (I) either alone or asmixtures in all proportions.

Too, the “effective” amount of compound administered corresponds to theamount required to elicit the desired result. One skilled in this art isthus capable of easily evaluating this effective amount, which dependson the nature of the compound used and on the particular individual thustreated.

To provide an order of magnitude, in the compositions according to theinvention, the compounds of formula (I) are advantageously present at aconcentration ranging from 0.001% to 10% by weight relative to the totalweight of the composition and preferably from 0.01% to 2%.

The present invention also features formulating as an active principle,in a physiologically acceptable medium (vehicle, diluent or carrier),into a composition, of an effective amount of at least one compound offormula (I); such compounds/compositions are well suited to induceand/or stimulate hair growth and/or prevent hair loss.

The compositions according to the invention can be ingested, injected ortopically applied onto the skin and/or the hair. Depending on the modeof administration, the compositions according to the invention areformulated into any pharmaceutical form normally employed.

For topical application onto the skin or the hair, the composition canbe in the form, in particular, of an aqueous or oily solution or adispersion of the lotion or serum type, emulsions of liquid orsemi-liquid consistency of the milk type, obtained by dispersing a fattyphase in an aqueous phase (O/W) or, conversely, (W/O), or suspensions oremulsions of runny consistency of the cream or aqueous or anhydrous geltype, or alternatively microcapsules or microparticles, or vesicledispersions of ionic and/or nonionic type. These compositions areformulated via the usual techniques.

They can also be used for the hair in the form of aqueous, alcoholic oraqueous-alcoholic solutions, or in the form of creams, gels, ointments,emulsions or mousses or alternatively in the form of aerosolcompositions also comprising a propellant under pressure.

The compositions according to the invention can also constitute ahaircare composition, in particular a shampoo, a hairsetting lotion, atreating lotion, a styling cream or gel, a dye composition (inparticular an oxidation dye composition) optionally in the form ofcoloring shampoos, restructuring lotions for the hair, apermanent-waving composition (in particular a composition for the firststage of a permanent-waving operation), a lotion or gel for preventinghair loss, an antiparasitic shampoo, etc.

For systemic injection, the subject compositions can be formulated as anaqueous or oily lotion or in the form of a serum. For the eyes, dropsare well suited, and for ingestion, same can be formulated as capsules,granules, syrups or tablets.

The amounts of the various constituents in the compositions according tothe invention are those conventional in the fields under consideration.

The compositions according to the invention can also be formulated assolid preparations constituting cleansing soaps or bars.

The subject compositions can also be packaged in the form of an aerosolcomposition also comprising a propellant under pressure.

When the composition is an emulsion, the proportion of the fatty phaseadvantageously ranges from 5% to 80% by weight and preferably from 5% to50% by weight relative to the total weight of the composition. The oils,waxes, emulsifiers and co-emulsifiers included in the composition inemulsion form are chosen from among those that are conventional in thecosmetics field. The emulsifier and the co-emulsifier are advantageouslypresent in the composition in a proportion ranging from 0.3% to 30% byweight, and preferably from 0.5% to 20% by weight, relative to the totalweight of the composition. The emulsion can also contain lipid vesicles.

When the composition is an oily solution or gel, the fatty phase canconstitute more than 90% of the total weight of the composition.

In known fashion, the subject compositions can also contain additivesand adjuvants that are common in the cosmetics field, such ashydrophilic or lipophilic gelling agents, hydrophilic or lipophilicadditives and active agents, preservatives, antioxidants, solvents,fragrances, fillers, sunscreening agents, odor absorbers and dyestuffsand colorants. The amounts of these various adjuvants are thoseconventionally formulated in the cosmetics field, and, for example,range from 0.01% to 10% of the total weight of the composition.Depending on their nature, these additives and adjuvants can beintroduced into the fatty phase, into the aqueous phase and/or into thelipid spherules.

Exemplary oils or waxes according to the invention include mineral oils(liquid petroleum jelly), plant oils (liquid fraction of karite butteror sunflower oil), animal oils (perhydrosqualene), synthetic oils(purcellin oil), silicone oils or waxes (cyclomethicone) and fluoro oils(perfluoropolyethers), beeswax, carnauba wax or paraffin wax. Fattyalcohols and fatty acids (stearic acid) can be added to these oils.Exemplary emulsifiers according to the invention include glycerylstearate, polysorbate-60 and the PEG-6/PEG-32/glycol stearate mixturemarketed under the trademark Tefose®63 by Gattefosse.

Exemplary solvents per this invention include the lower alcohols, inparticular ethanol and isopropanol, and propylene glycol.

And exemplary hydrophilic gelling agents include carboxyvinyl polymers(carbomer), acrylic copolymers such as acrylate/alkylacrylatecopolymers, polyacrylamides, polysaccharides such ashydroxy-propylcellulose, natural gums and clays, and exemplarylipophilic gelling agents include modified clays such as bentones, metalsalts of fatty acids, such as aluminum stearates, and hydrophobicsilica, ethylcellulose and polyethylene.

The subject compositions can contain other hydrophilic active agents,such as proteins or protein hydrolysates, amino acids, polyols, urea,allantoin, sugars and sugar derivatives, water-soluble vitamins, plantextracts and hydroxy acids.

Lipophilic active agents which are suitable include retinol (vitamin A)and derivatives thereof, tocopherol (vitamin E) and derivatives thereof,essential fatty acids, ceramides, essential oils and salicylic acid andits derivatives.

In one embodiment according to the invention, the subject compositionscomprise at least one compound of formula (I) in admixture with otheractive agents. Among these active agents, particularly representativeare:

(1) agents for improving the activity with regard to regrowth of thehair and/or preventing hair loss, and which have already been describedfor such activity, for example, nicotinic acid esters, including, inparticular, tocopheryl nicotinate, benzyl nicotinate and C₁-C₆ alkylnicotinates such as methyl or hexyl nicotinates, pyrimidine derivatives,such as 2,4-diamino-6-piperidinopyrimidine 3-oxide or “Minoxidil”described in U.S. Pat. Nos. 4,139,619 and 4,596,812, and agents forpromoting regrowth of the hair, such as those described in the Europeanpatent application published under No. 0,648,488 and assigned to theassignee hereof;

(2) agents which reduce skin differentiation and/or proliferation and/orpigmentation, such as retinoic acid and its isomers, retinol and itsesters, vitamin D and derivatives thereof, estrogens such as estradiol,kojic acid or hydroquinone;

(3) antibacterial agents such as clindamycin phosphate, erythromycin orantibiotics of the tetracyclene class;

(4) antiparasitic agents, in particular metronidazole, crotamiton orpyrethroids;

(5) antifungal agents, in particular compounds belonging to theimidazole class, such as econazole, ketoconazole or miconazole or theirsalts, polyene compounds, such as amphotericin B, compounds of theallylamine family such as terbinafine, or alternatively octopirox;

(6) antiviral agents such as acyclovir;

(7) steroidal anti-inflammatory agents such as hydrocortisone,betamethasone valerate or clobetasol propionate, or nonsteroidalanti-inflammatory agents such as, for example, ibuprofen and its salts,diclofenac and its salts, acetylsalicylic acid, acetaminophen orglycyrrhizic acid;

(8) anaesthetics such as lidocane hydrochloride and derivatives thereof;

(9) anti-pruriginous agents such as thenaldine, trimeprazine orcyproheptadine;

(10) keratolytic agents such as α- and β-hydroxycarboxylic orβ-ketocarboxylic acids, their salts, amides or esters and moreparticularly hydroxy acids such as glycolic acid, lactic acid, salicylicacid, citric acid and fruit acids in general, and 5-n-octanoylsalicylicacid;

(11) anti-free-radical agents such as α-tocopherol or its esters,superoxide dismutases, certain metal-chelating agents or ascorbic acidand its esters;

(12) antiseborrhoeic agents such as progesterone;

(13) antidandruff agents such as octopirox or zinc pyrithione;

(14) antiacne agents such as retinoic acid or benzoyl peroxide;

(15) extracts of plant, marine or bacterial origin.

Other compounds may also be included, for example, Diazoxide,Spiroxazone, phospholipids such as lecithin, linoleic acid, linolenicacid, salicylic acid and derivatives thereof described in FR-2,581,542,e.g., salicylic acid derivatives bearing an alkanoyl group containingfrom 2 to 12 carbon atoms in the 5-position of the benzene ring,hydroxycarboxylic or ketocarboxylic acids and their esters, lactones andtheir corresponding salts, anthralin, carotenoids, eicosatetraenoic andeicosatrienoic acids or their esters and amides.

Thus, in one specific embodiment, the compositions according to theinvention also comprise at least one active agent or substrate selectedfrom among antibacterial agents, antiparasitic agents, antifungalagents, antiviral agents, anti-inflammatory agents, antipruriginousagents, anaesthetics, keratolytic agents, anti-free-radical agents,antiseborrhoeic agents, antidandruff agents, antiacne agents and/oragents for reducing skin differentiation and/or proliferation and/orpigmentation, and extracts of plant, marine or bacterial origin.

It will also be appreciated that the subject compositions can compriseat least one compound as described above in liposomal form, inparticular as described in WO-94/22468, filed Oct. 13, 1994 by AntiCancer Inc. Thus, the compound encapsulated in the liposomes can bedelivered selectively to the hair follicle.

The compositions according to the invention are topically applied ontothe alopecic areas of an individual subject's scalp and hair, and isoptionally maintained in contact with such areas for several hours andoptionally rinsed therefrom. In one embodiment, a composition containingan effective amount of at least one compound as described above istopically applied during the evening, maintained overnight andoptionally shampooed out in the morning. These applications can berepeated daily for one or more months depending on the needs of theindividual.

Thus, the present invention also features a cosmetic treatment for thehair and/or the scalp (regime or regimen), comprising topically applyinga composition containing an effective amount of at least one compound asdescribed above to the hair and/or the scalp, maintaining thiscomposition in contact with the hair and/or the scalp and optionallyrinsing same therefrom.

This treatment has the characteristics of a cosmetic regime/regimeninasmuch as it improves the aesthetics of the hair by providing morevitality and imparting an improved appearance thereto.

The compositions according to the invention are well suited for cosmeticor pharmaceutical applications, in particular dermatologicalapplication.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

EXAMPLE 1 Synthesis of 2-amino-4-hexylaminopyrimidine 3-oxide

(1) Preparation of 2-amino-4-hexylamino-6-chloropyrimidine

50 g of 2-amino-4,6-dichloropyrimidine were suspended in 350 ml ofabsolute ethanol in a reactor. 181.5 ml of hexylamine (reagent A) wereadded in a single portion and the mixture was refluxed for 3 h. Themedium was evaporated under vacuum. The oil obtained was taken up in 600ml of water with stirring for 1 h, 30 min. The precipitate was filteredoff, washed and dried in a heated desiccator. 43.5 g of the expectedcompound were thus obtained, for a yield of 62%.

Analysis

*NMR spectrum: ¹H (200 MHz; DMSO) δ ppm 0.8 (3H, t), 1.2 (6H, s), 1.4(2H, t), 3(2H, s), 5.6 (1H, s), 6.2 (2H, s), 6.9 (1H, s).

(2) Preparation of 2-amino-4-hexylamino-6-chloropyrimidine 3-oxide

5.95 g of urea/H₂O₂ complex and 9.07 g of phthalic anhydride weresuspended in 90 ml of isopropanol, in a three-necked flask. The mixturewas stirred for 30 min at room temperature (20-25° C.). 10 g of2-amino-4-hexylamino-6-chloropyrimidine were then added whilecontrolling the exotherm at +30° C. After reaction for 3 hours, 100 mlof sodium hydrogen sulfite were poured thereinin to destroy the residualoxidizing agents. The mixture was permitted to separate out by settlingand the upper phase was concentrated under vacuum. The residue obtainedwas taken up in a water (80 ml)/30% sodium hydroxide (20 ml) mixture.The solid obtained was reimpasted in 150 ml of isopropyl ether. Thesolid was filtered off and washed. It was dried in a heated desiccator.4.52 g of the expected compound were thus obtained, for a yield of 42%.

Analysis

*NMR spectrum ¹H (200 MHz; DMSO) δ ppm 0.7 (3H, t), 1 (6H, s), 1.2 (2H,t), 3.1(2H, m), 6 (1H, s), 7.4 (2H,m), 7.7 (1H, t).

(3) Synthesis of 2-amino-4-hexylaminopyrimidine 3-oxide

0.7 g of potassium hydroxide was dissolved in 100 ml of absoluteethanol, in a three-necked flask. 2.2 g of2-amino-4-hexylamino-6-chloropyrimidine 3-oxide were then added. Aftercomplete dissolution, 0.5 g of palladium-on-charcoal was added and themixture was reacted in a hydrogenator at a hydrogen pressure of 3 bar.After 2 hours, the medium was filtered through filter paper andconcentrated under vacuum. The pale yellow solid obtained wasrecrystallized from 20 ml of acetonitrile. It was filtered off and thefilter cake was washed with 10 ml of water. The solid was dried in adesiccator under vacuum. 1 g of the expected compound was thus obtained,for a yield of 53%.

Analysis

*NMR spectrum: ¹H (200 MHz; DMSO) δ ppm; 1.9 (3H, t), 2.2 (6H, s), 2.5(2H, t), 4.3 (2H, m), 7.2 (1H, d), 8.1 (2H, s), 8.5 (1H, d), 8.6 (1H,m).

EXAMPLE 2 Synthesis of 2-amino-4-dodecylaminopyrimidine 3-oxide

(1) Preparation of 2-amino-4-dodecylamino-6-chloropyrimidine

10 g of 2-amino-4,6-dichloropyrimidine were suspended in 100 ml ofabsolute ethanol in a reactor. 33.9 g of dodecylamine (reagent A) wereadded in a single portion and the mixture was refluxed for 2 h. Themedium was evaporated under vacuum. The solid obtained was taken up in200 ml of acetone with stirring for 30 min. 200 ml of water were addedand the mixture was maintained under stirring for 2 h. The solid wasfiltered off, washed and dried in a heated desiccator.

17.55 g of the expected compound were thus obtained, for a yield of 92%.

Analysis

*NMR spectrum: ¹H (200 MHz; DMSO) δ ppm; 0.8 (3H, t), 1.2 (18H, s), 1.3(2H, t), 3 (2H,s), 5.6 (1H, s), 6.1 (2H, s), 6.8 (1H, s).

(2) Preparation of 2-amino-4-dodecylamino-6-chloropyrimidine 3-oxide

3.26 g of urea/H₂O₂ complex and 4.97 g of phthalic anhydride weresuspended in 60 ml of isopropanol, in a three-necked flask. The mixturewas maintained under stirring for 30 min at room temperature. 10 g of2-amino-4-dodecylamino-6-chloropyrimidine were then added whilecontrolling the exotherm at +25° C. After reaction for 2 hours, themedium was cooled to +4° C. for 1 h. The solid was filtered off andwashed with 5 ml of ice-cold methanol. The solid was taken up in a water(12 ml)/40% sodium hydroxide (3 ml) mixture. The solid was filtered offand washed. It was dried in a heated desiccator.

3.3 g of the expected compound were thus obtained, for a yield of 42%.

Analysis

*NMR spectrum ¹H (200 MHz; DMSO) δ ppm; 0.7 (3H, t), 1.1 (18H, s), 1.3(2H, t), 2.8 (2H,t), 5.5 (1H, s), 6.9 (3H, m).

(3) Synthesis of 2-amino-4-dodecylaminopyrimidine 3-oxide

0.7 g of potassium hydroxide was dissolved in 250 ml of absoluteethanol, in a three-necked flask. 3.3 g of2-amino-4-dodecylamino-6-chloropyrimidine 3-oxide were then added. Oncedissolution was complete, 0.5 g of palladium-on-charcoal was added andthe mixture was reacted in a hydrogenator at a hydrogen pressure of 3bar. After 2 h, the medium was filtered through filter paper andconcentrated under vacuum. The solid obtained was recrystallized from anethanol (10 ml)/acetonitrile (50 ml) mixture. It was filtered off andthe filter cake was washed with 10 ml of water. The solid was dried in adesiccator under vacuum.

0.8 g of the expected compound was thus obtained, for a yield of 27%.

Analysis

*NMR spectrum: ¹H (200 MHz; DMSO) δ ppm; 0.9 (3H, t), 1.3 (18H, s), 1.7(2H, t), 3.3 (2H, m), 6.3 (1H, d), 7.2 (2H, s), 7.6 (1H, d), 7.7 (1H,m).

EXAMPLE 3 Synthesis of 2-amino-4-octylaminopyrimidine 3-oxide

(1) Preparation of 2-amino-4-octylamino-6-chloropyrimidine

20 g of 2-amino-4,6-dichloropyrimidine were suspended in 200 ml ofabsolute ethanol in a reactor. 60 g of octylamine (reagent A) were addedin a single portion and the mixture was refluxed for 2 h. The medium wasevaporated under vacuum. The oil obtained was extracted withdichloromethane and was then purified on a column of silica.

22.8 g of the expected compound were thus obtained, for a yield of 71%.

Analysis

NMR: ¹H (200 MHz; CDCl₃) δ ppm; 1 (3H, t), 1.4 (10H, s), 1.7 (2H, t),3.3 (2H, m), 5.1 (3H, d), 6 (1H, s).

(2) Preparation of 2-amino-4-octylamino-6-chloropyrimidine 3-oxide

6.8 g of urea/H₂O₂ complex and 10.35 g of phthalic anhydride weresuspended in 100 ml of isopropanol, in a three-necked flask. The mixturewas maintained stirring for 30 min at room temperature. 10 g of2-amino-4-octylamino-6-chloropyrimidine were then added, whilecontrolling the exotherm at +30° C. After reaction for 3 hours, 100 mlof sodium hydrogen sulfite were poured thereinin to destroy the residualoxidizing agents. The mixture was permitted to separate by settling andthe upper phase was concentrated under vacuum. The residue obtained wastaken up in a water (80 ml)/30% sodium hydroxide (20 ml) mixture. Thesolid was filtered off and washed. This solid was dried in a heateddesiccator.

6.3 g of the expected compound were thus obtained, for a yield of 46%.

Analysis

NMR: ¹H (200 MHz; DMSO) δ ppm; 0.7 (3H, t), 1.1 (10H, s), 1.4 (2H, t),3(2H, t), 6 (1H, s), 7.2 (3H, s).

(3) Synthesis of 2-amino-4-octylaminopyrimidine 3-oxide

0.54 g of potassium hydroxide was dissolved in 100 ml of absoluteethanol, in a three-necked flask. 2 g of2-amino-4-octylamino-6-chloropyrimidine 3-oxide were then added. Oncedissolution was complete, 0.5 g of palladium-on-charcoal was added andthe mixture was reacted in a hydrogenator at a hydrogen pressure of 3bar. After 2 hours, the medium was filtered through filter paper andconcentrated under vacuum. The pale yellow solid obtained wasrecrystallized from 20 ml of acetonitrile. It was filtered off and thefilter cake was washed with 10 ml of water. The solid was dried in adesiccator under vacuum.

0.5 g of the expected compound was thus obtained, for a yield of 29%.

Analysis

NMR: ¹H (200 MHz; DMSO) δ ppm; 1.1 (3H, t), 1.4 (10H, s), 1.8 (2H, t),3.4 (2H, m), 6.1 (1H, d), 6.4 (2H, s), 7.3 (1H, t), 7.7 (1H, d).

EXAMPLES 4-16

The following compounds of the invention listed below are obtained viathe same procedure as in Examples 1-3 and using the appropriate reagentA in the first step of the process (see Table I below):

TABLE I Compound obtained Reagent A used 42-amino-4-pentylaminopyrimidine 3-oxide pentylamine 52-amino-4-heptylaminopyrimidine 3-oxide heptylamine 62-amino-4-nonylaminopyrimidine 3-oxide nonylamine 72-amino-4-decylaminopyrimidine 3-oxide decylamine 82-amino-4-undecylaminopyrimidine 3-oxide undecylamine 92-amino-4-tridecylaminopyrimidine 3-oxide tridecylamine 102-amino-4-tetradecylaminopyrimidine 3-oxide tetradecylamine 112-amino-4-pentadecylaminopyrimidine 3-oxide pentadecylamine 122-amino-4-hexadecylaminopyrimidine 3-oxide hexadecylamine 132-amino-4-heptadecylaminopyrimidine 3-oxide heptadecylamine 142-amino-4-octadecylaminopyrimidine 3-oxide octadecylamine 152-amino-4-nonadecylaminopyrimidine 3-oxide nonadecylamine 162-amino-4-eicosadecylaminopyrimidine 3-oxide eicosadecyl- amine

EXAMPLE 17 Synthesis of 2-amino-4-octylamino-6-butyloxypyrimidine3-oxide

TABLE I Compound obtained Reagent A used 42-amino-4-pentylaminopyrimidine 3-oxide pentylamine 52-amino-4-heptylaminopyrimidine 3-oxide heptylamine 62-amino-4-nonylaminopyrimidine 3-oxide nonylamine 72-amino-4-decylaminopyrimidine 3-oxide decylamine 82-amino-4-undecylaminopyrimidine 3-oxide undecylamine 92-amino-4-tridecylaminopyrimidine 3-oxide tridecylamine 102-amino-4-tetradecylaminopyrimidine 3-oxide tetradecylamine 112-amino-4-pentadecylaminopyrimidine 3-oxide pentadecylamine 122-amino-4-hexadecylaminopyrimidine 3-oxide hexadecylamine 132-amino-4-heptadecylaminopyrimidine 3-oxide heptadecylamine 142-amino-4-octadecylaminopyrimidine 3-oxide octadecylamine 152-amino-4-nonadecylaminopyrimidine 3-oxide nonadecylamine 162-amino-4-eicosadecylaminopyrimidine 3-oxide eicosadecyl- amine

90 ml of butanol (reagent B) predried over K₂CO₃ were introduced into a250 ml three-necked flask. 0.18 g of sodium in kerosene was addedportionwise under argon. The medium was then heated at 60° C. until thesodium has completely dissolved.

1.5 g of 2-amino-4-octylamino-6-chloropyrimidine 3-oxide, obtainedaccording to Example 3 (reagent C), was then introduced and the mixturewas heated at 90° C. for 24 hours.

The medium was washed with aqueous 20% sodium chloride solution and thebutanol phase was then concentrated on a rotavapor. The residue obtainedwas purified on a column of silica. The oily product obtained at thecolumn outlet was dissolved in 2.2 ml (2.5 eq) of 2N hydrochloricmethanol solution and the solution was then evaporated under reducedpressure. An off-white solid was obtained, which was washed with 10 mlof isopropyl ether. 0.5 g of a white solid of the expected compound wasobtained, in a yield of 30%.

Analysis

NMR: ¹H (200 MHz; DMSO) δ ppm; 1 (6H, m), 1.7 (2H, s), 6.1 (16H, m), 3.4(2H, q), 4.3 (2H;t), 5.7 (1H;s), 8.5 (4H;m).

Elemental Analysis (1 Hcl)

C H N O Cl Theoretical 55.40% 9.01% 16.15% 9.22% 10.22% Found 55.19%8.88% 16.07% 9.94%

EXAMPLES 18 to 80

The following compounds of the invention listed below (Table II) areobtained via the same procedure as in Example 17, but using theappropriate reagent A in the first step of the process and theappropriate reagents B and C in the 2nd step (see Table III below).

TABLE II Example Compound obtained 182-amino-4-pentylamino-6-methoxypyrimidine 3-oxide 192-amino-4-hexylamino-6-methoxypyrimidine 3-oxide 202-amino-4-heptylamino-6-methoxypyrimidine 3-oxide 212-amino-4-octylamino-6-methoxypyrimidine 3-oxide 222-amino-4-nonylamino-6-methoxypyrimidine 3-oxide 232-amino-4-decylamino-6-methoxypyrimidine 3-oxide 242-amino-4-undecylamino-6-methoxypyrimidine 3-oxide 252-amino-4-dodecylamino-6-methoxypyrimidine 3-oxide 262-amino-4-tridecylamino-6-methoxypyrimidine 3-oxide 272-amino-4-tetradecylamino-6-methoxypyrimidine 3-oxide 282-amino-4-pentadecylamino-6-methoxypyrimidine 3-oxide 292-amino-4-hexadecylamino-6-methoxypyrimidine 3-oxide 302-amino-4-heptadecylamino-6-methoxypyrimidine 3-oxide 312-amino-4-octadecylamino-6-methoxypyrimidine 3-oxide 322-amino-4-nonadecylamino-6-methoxypyrimidine 3-oxide 332-amino-4-eicosadecylamino-6-methoxypyrimidine 3-oxide 342-amino-4-pentylamino-6-ethoxypyrimidine 3-oxide 352-amino-4-hexylamino-6-ethoxypyrimidine 3-oxide 362-amino-4-heptylamino-6-ethoxypyrimidine 3-oxide 372-amino-4-octylamino-6-ethoxypyrimidine 3-oxide 382-amino-4-nonylamino-6-ethoxypyrimidine 3-oxide 392-amino-4-decylamino-6-ethoxypyrimidine 3-oxide 402-amino-4-undecylamino-6-ethoxypyrimidine 3-oxide 412-amino-4-dodecylamino-6-ethoxypyrimidine 3-oxide 422-amino-4-tridecylamino-6-ethoxypyrimidine 3-oxide 432-amino-4-tetradecylamino-6-ethoxypyrimidine 3-oxide 442-amino-4-pentadecylamino-6-ethoxypyrimidine 3-oxide 452-amino-4-hexadecylamino-6-ethoxypyrimidine 3-oxide 462-amino-4-heptadecylamino-6-ethoxypyrimidine 3-oxide 472-amino-4-octadecylamino-6-ethoxypyrimidine 3-oxide 482-amino-4-nonadecylamino-6-ethoxypyrimidine 3-oxide 492-amino-4-eicosadecylamino-6-ethoxypyrimidine 3-oxide 502-amino-4-pentylamino-6-propyloxypyrimidine 3-oxide 512-amino-4-hexylamino-6-propyloxypyrimidine 3-oxide 522-amino-4-heptylamino-6-propyloxypyrimidine 3-oxide 532-amino-4-octylamino-6-propyloxypyrimidine 3-oxide 542-amino-4-nonylamino-6-propyloxypyrimidine 3-oxide 552-amino-4-decylamino-6-propyloxypyrimidine 3-oxide 562-amino-4-undecylamino-6-propyloxypyrimidine 3-oxide 572-amino-4-dodecylamino-6-propyloxypyrimidine 3-oxide 582-amino-4-tridecylamino-6-propyloxypyrimidine 3-oxide 592-amino-4-tetradecylamino-6-propyloxypyrimidine 3-oxide 602-amino-4-pentadecylamino-6-propyloxypyrimidine 3-oxide 612-amino-4-hexadecylamino-6-propyloxypyrimidine 3-oxide 622-amino-4-heptadecylamino-6-propyloxypyrimidine 3-oxide 632-amino-4-octadecylamino-6-propyloxypyrimidine 3-oxide 642-amino-4-nonadecylamino-6-propyloxypyrimidine 3-oxide 652-amino-4-eicosadecylamino-6-propyloxypyrimidine 3-oxide 662-amino-4-pentylamino-6-butyloxypyrimidine 3-oxide 672-amino-4-hexylamino-6-butyloxypyrimidine 3-oxide 682-amino-4-heptylamino-6-butyloxypyrimidine 3-oxide 692-amino-4-nonylamino-6-butyloxypyrimidine 3-oxide 702-amino-4-decylamino-6-butyloxypyrimidine 3-oxide 712-amino-4-undecylamino-6-butyloxypyrimidine 3-oxide 722-amino-4-dodecylamino-6-butyloxypyrimidine 3-oxide 732-amino-4-tridecylamino-6-butyloxypyrimidine 3-oxide 742-amino-4-tetradecylamino-6-butyloxypyrimidine 3-oxide 752-amino-4-pentadecylamino-6-butyloxypyrimidine 3-oxide 762-amino-4-hexadecylamino-6-butyloxypyrimidine 3-oxide 772-amino-4-heptadecylamino-6-butyloxypyrimidine 3-oxide 782-amino-4-octadecylamino-6-butyloxypyrimidine 3-oxide 792-amino-4-nonadecylamino-6-butyloxypyrimidine 3-oxide 802-amino-4-eicosadecylamino-6-butyloxypyrimidine 3-oxide

TABLE III Example Reagent A Reagent B Reagent C 18 pentylamine methanol2-amino-4-pentylamino-6-chloro- pyrimidine 3-oxide 19 hexylaminemethanol 2-amino-4-hexylamino-6-chloro- pyrimidine 3-oxide 20heptylamine methanol 2-amino-4-heptylamino-6-chloro- pyrimidine 3-oxide21 octylamine methanol 2-amino-4-octylamino-6-chloro- pyrimidine 3-oxide22 nonylamine methanol 2-amino-4-nonylamino-6-chloro- pyrimidine 3-oxide23 decylamine methanol 2-amino-4-decylamino-6-chloro- pyrimidine 3-oxide24 undecylamine methanol 2-amino-4-undecylamino-6-chloro- pyrimidine3-oxide 25 dodecylamine methanol 2-amino-4-dodecylamino-6-chloropyrimidine 3-oxide 26 tridecylamine methanol2-amino-4-tridecylamino-6-chloro- pyrimidine 3-oxide 27 tetradecyl-methanol 2-amino-4-tetradecylamino-6- amine chloropyrimidine 3-oxide 28pentadecyl- methanol 2-amino-4-pentadecylamino-6- amine chloropyrimidine3-oxide 29 hexadecyl- methanol 2-amino-4-hexadecylamino-6-chloro- aminepyrimidine 3-oxide 30 heptadecyl- methanol 2-amino-4-heptadecylamino-6-amine chloropyrimidine 3-oxide 31 octadecyl- methanol2-amino-4-octadecylamino-6-chloro- amine pyrimidine 3-oxide 32nonadecyl- methanol 2-amino-4-nonadecylamino-6-chloro- amine pyrimidine3-oxide 33 eicosadecyl- methanol 2-amino-4-eicosadecylamino-6- aminechloropyrimidine 3-oxide 34 pentylamine ethanol2-amino-4-pentylamino-6-chloro- pyrimidine 3-oxide 35 hexylamine ethanol2-amino-4-hexylamino-6-chloro- pyrimidine 3-oxide 36 heptylamine ethanol2-amino-4-heptylamino-6-chloro- pyrimidine 3-oxide 37 octylamine ethanol2-amino-4-octylamino-6-chloro- pyrimidine 3-oxide 38 nonylamine ethanol2-amino-4-nonylamino-6-chloro- pyrimidine 3-oxide 39 decylamine ethanol2-amino-4-decylamino-6-chloro- pyrimidine 3-oxide 40 undecylamineethanol 2-amino-4-undecylamino-6-chloro- pyrimidine 3-oxide 41dodecylamine ethanol 2-amino-4-dodecylamino-6-chloro- pyrimidine 3-oxide42 tridecylamine ethanol 2-amino-4-tridecylamino-6-chloro- pyrimidine3-oxide 43 tetradecyl- ethanol 2-amino-4-tetradecylamino-6- aminechloropyrimidine 3-oxide 44 pentadecyl- ethanol2-amino-4-pentadecylamino-6- amine chloropyrimidine 3-oxide 45hexadecyl- ethanol 2-amino-4-hexadecylamino-6-chloro- amine pyrimidine3-oxide 46 heptadecyl- ethanol 2-amino-4-heptadecylamino-6- aminechloropyrimidine 3-oxide 47 octadecyl- ethanol2-amino-4-octadecylamino-6-chloro- amine pyrimidine 3-oxide 48nonadecyl- ethanol 2-amino-4-nonadecylamino-6-chloro- amine pyrimidine3-oxide 49 eicosadecyl- ethanol 2-amino-4-eicosadecylamino-6- aminechloropyrimidine 3-oxide 50 pentylamine propanol2-amino-4-pentylamino-6-chloro- pyrimidine 3-oxide 51 hexylaminepropanol 2-amino-4-hexylamino-6-chloro- pyrimidine 3-oxide 52heptylamine propanol 2-amino-4-heptylamino-6-chloro- pyrimidine 3-oxide53 octylamine propanol 2-amino-4-octylamino-6-chloro- pyrimidine 3-oxide54 nonylamine propanol 2-amino-4-nonylamino-6-chloro- pyrimidine 3-oxide55 decylamine propanol 2-amino-4-decylamino-6-chloro- pyrimidine 3-oxide56 undecylamine propanol 2-amino-4-undecylamino-6-chloro- pyrimidine3-oxide 57 dodecylamine propanol 2-amino-4-dodecylamino-6-chloro-pyrimidine 3-oxide 58 tridecylamine propanol2-amino-4-tridecylamino-6-chloro- pyrimidine 3-oxide 59 tetradecyl-propanol 2-amino-4-tetradecylamino-6- amine chloropyrimidine 3-oxide 60pentadecyl- propanol 2-amino-4-pentadecylamino-6- amine chloropyrimidine3-oxide 61 hexadecyl- propanol 2-amino-4-hexadecylamino-6-chloro- aminepyrimidine 3-oxide 62 heptadecyl- propanol 2-amino-4-heptadecylamino-6-amine chloropyrimidine 3-oxide 63 octadecyl- propanol2-amino-4-octadecylamino-6-chloro- amine pyrimidine 3-oxide 64nonadecyl- propanol 2-amino-4-nonadecylamino-6-chloro- amine pyrimidine3-oxide 65 eicosadecyl- propanol 2-amino-4-eicosadecylamino-6- aminechloropyrimidine 3-oxide 66 pentylamine butanol2-amino-4-pentylamino-6-chloro- pyrimidine 3-oxide 67 hexylamine butanol2-amino-4-hexylamino-6-chloro- pyrimidine 3-oxide 68 heptylamine butanol2-amino-4-heptylamino-6-chloro- pyrimidine 3-oxide 69 nonylamine butanol2-amino-4-nonylamino-6-chloro- pyrimidine 3-oxide 70 decylamine butanol2-amino-4-decylamino-6-chloro- pyrimidine 3-oxide 71 undecylaminebutanol 2-amino-4-undecylamino-6-chloro- pyrimidine 3-oxide 72dodecylamine butanol 2-amino-4-dodecylamino-6-chloro- pyrimidine 3-oxide73 tridecylamine butanol 2-amino-4-tridecylamino-6-chloro- pyrimidine3-oxide 74 tetradecyl- butanol 2-amino-4-tetradecylamino-6- aminechloropyrimidine 3-oxide 75 pentadecyl- butanol2-amino-4-pentadecylamino-6- amine chloropyrimidine 3-oxide 76hexadecyl- butanol 2-amino-4-hexadecylamino-6-chloro- amine pyrimidine3-oxide 77 heptadecyl- butanol 2-amino-4-heptadecylamino-6- aminechloropyrimidine 3-oxide 78 octadecyl- butanol2-amino-4-octadecylamino-6-chloro- amine pyrimidine 3-oxide 79nonadecyl- butanol 2-amino-4-nonadecylamino-6-chloro- amine pyrimidine3-oxide 80 eicosadecyl- butanol 2-amino-4-eicosadecylamino-6- aminechloropyrimidine 3-oxide

EXAMPLE 81

Measurement of the prostaglandin-endoperoxide synthase (PGHS-1)activating power.

General Measuring Principles

The amount of oxygen required for the oxidation of arachidonic acid wasmeasured by means of the cyclooxygenase activity of theprostaglandin-endoperoxide synthase, in the presence or absence of thetest compound.

The oxygen consumption measurements were taken using a Clark electrodeconnected to a YSI 5300 oxymeter marketed by Yellow Spring Instruments.

These measurements were taken in an open chamber with constant stirringat a temperature of 37° C.

If a graph recorder was used, the oxygen consumption measurement isexpressed in the form of a curve, the maximum slope of which makes itpossible to determine the initial rate of the reaction, and from whichit is possible to calculate the period for which the initial reactionrate is maintained.

The curve thus obtained, in the absence of any substance other than theingredients required for the enzymatic reaction, provides the basalactivity of the enzyme. The initial rate and the period for which thisrate is maintained can be determined under these conditions in areaction comprising only the enzyme and its substrate.

These data will serve as a reference in the study of the test compounds.

The activity of the test compounds was measured under the sameconditions, by adding the test compound to the reaction medium. Theactivity of the test compound with respect to cyclooxygenase wasevaluated by means of the variation of the slope and the variation ofthe period for which the maximum rate was maintained.

Formulation for the Measurements

A solution of 0.1 M Tris and 5 mM EDTA at pH=8.00 (TE solution) wasprepared.

The measurements were taken in a buffered solution (TEA buffer) composedof 9 volumes of TE solution and 1 volume of 20% alcohol.

The substrate was formulated in the form of a stock solution ofpotassium arachidonate according to the supplier's procedure (Interchim,France).

The solution thus obtained had a 46 mM titre of arachidonic acid. It canbe stored at 4° C. for 24 hours.

The enzyme employed was prostaglandin endoperoxidesynthase (PGHS-1),isolated from sheep seminal glands, marketed by Cayman Chemical underthe reference 60100.

The test compounds were prepared in the form of a stock solution with atitre of 5 mM, in a water/alcohol mixture (80/20) and were tested withthe same batch of enzyme.

Measurements

Basal Activities of the Enzyme

At t=0, 380 μl of TEA buffer preheated to 37° C. were introduced intothe measuring chamber and maintained to equilibrate for at least oneminute.

At t=1, 300 units of enzyme (PGHS) were introduced.

Recording was initiated, and the mixture was again permitted tostabilize for one minute. The recording obtained provided the reactionbaseline.

After a further minute, 10 μl of substrate were introduced and theoxygen consumption was recorded for 2 to 3 minutes.

The initial reaction rate and the period for which this rate wasmaintained were thus determined. These data served as a reference forthe measurements of the activity of the test compounds.

Activities of the Test Compounds

The experimental conditions were identical to those above, except thatthe TEA buffer preheated to 37° C. was replaced by an identical buffercontaining the test compound at a concentration of 0.5 mM.

Results

The following results are expressed as a % relative to the valuesobtained with the control.

TABLE IV Compounds Activation Control  +0% Compound of Example 1 +37%Compound of Example 2 +11% Compound of Example 3 +14% Compound ofExample 17  +8% Indomethacin¹ −100% ¹1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid, orindomethacin, is a known inhibitor of cyclooxygenase activity. (H. P.Rang/M. M. Dale Pharmacology second edition 1991. Published by ChurchillLivingstone.) This inhibitory effect was clearly evident under theconditions of the experiments.

EXAMPLE 82

The following specific compositions containing at least one2-amino-4-alkylaminopyrimidine 3-oxide of the invention were formulatedemploying conventional techniques in the cosmetics or pharmacy arts.

Lotion for Preventing Hair Loss

Compound of Example 2 0.5 g Propylene glycol 10.0 g Isopropyl alcohol qs100.0 g

1 ml of this lotion is applied to the scalp, at a frequency of once ortwice a day.

Niosomal Gel

Chimexane NS ® 1.8 g Monosodium stearylglutamate 0.2 g Compound ofExample 17 2.0 g Carbomer 0.2 g Triethanolamine qs pH = 7 Preservativesqs Fragrances qs Demineralized water qs 100.0 g

This gel is applied to the scalp once or twice a day.

Lotion for Preventing Hair Loss

Compound of Example 17 3.0 g Propylene glycol 30.0 g Ethyl alcohol 40.5g Water qs 100.0 g

This lotion is applied to the scalp once or twice a day, at a rate of 1ml per application.

Thickened Lotion for Preventing Hair Loss

Compound of Example 2 1.0 g Kawain 2.0 g Hydroxypropylcellulose marketedby 3.5 g Hercules under the trademark Klucel G Ethyl alcohol qs 100.0 g

This thickened lotion is applied to the scalp once or twice a day, at arate of 1 ml per application.

Niosomal Lotion

Chimexane NL ® 0.475 g Cholesterol 0.475 g Monosodium stearylglutamate0.05 g Compound of Example 1 1.0 g Preservatives qs Dyes qs Fragrance qsDemineralized water qs 100.0 g

This lotion is applied to the scalp once or twice a day, at a rate of 1ml per application.

Lotion for Preventing Hair Loss

Compound of Example 3 1.0 g Propylene glycol monomethyl ether 20.0 gmarketed under the trademark Dowanol PM by Dow ChemicalHydroxypropylcellulose marketed by 3.0 g Hercules under the trademarkKlucel G Ethyl alcohol 40.0 g Water qs 100.0 g

This thickened lotion is applied to the scalp once or twice a day, at arate of 1 ml per application. While the invention has been described interms of various preferred embodiments, the skilled artisan willappreciate that various modifications, substitutions, omissions, andchanges may be made without departing from the spirit thereof.Accordingly, it is intended that the scope of the present invention belimited solely by the scope of the following claims, includingequivalents thereof.

What is claimed is:
 1. A 2-amino-4-alkylaminopyrimidine 3-oxide compoundhaving the structural formula (I):

in which R₁, is an alkyl radical having from 5 to 20 carbon atoms, and Zis a radical —OR₂, wherein R₂ is an alkyl radical having from 1to 12carbon atoms, and the acyl derivatives and acid addition salts thereof.2. The compound as defined by claim 1, wherein formula (I), R₁ is analkyl radical having from 6 to 12 carbon atoms.
 3. A compound as definedby claim 1, selected from among:2-amino-4-pentylamino-6-methoxypyrimidine 3-oxide;2-amino-4-hexylamino-6-methoxypyrimidine 3-oxide;2-amino-4-heptylamino-6-methoxypyrimidine 3-oxide;2-amino-4-octylamino-6-methoxypyrimidine 3-oxide;2-amino-4-nonylamino-6-methoxypyrimidine 3-oxide;2-amino-4-decylamino-6-methoxypyrimidine 3-oxide;2-amino-4-undecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-dodecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-tridecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-tetradecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-pentadecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-hexadecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-heptadecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-octadecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-nonadecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-eicosadecylamino-6-methoxypyrimidine 3-oxide;2-amino-4-pentylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-hexylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-heptylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-octylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-nonylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-decylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-undecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-dodecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-tridecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-tetradecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-pentadecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-hexadecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-heptadecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-octadecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-nonadecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-eicosadecylamino-6-ethoxypyrimidine 3-oxide;2-amino-4-pentylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-hexylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-heptylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-octylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-nonylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-decylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-undecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-dodecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-tridecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-tetradecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-pentadecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-hexadecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-heptadecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-octadecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-nonadecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-eicosadecylamino-6-propyloxypyrimidine 3-oxide;2-amino-4-pentylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-hexylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-heptylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-nonylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-decylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-undecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-dodecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-tridecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-tetradecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-pentadecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-hexadecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-heptadecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-octadecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-nonadecylamino-6-butyloxypyrimidine 3-oxide;2-amino-4-eicosadecylamino-6-butyloxypyrimidine 3-oxide; and thebranched isomers thereof.
 4. A compound as defined by claim 3,comprising 2-amino-4-octylamino-6-butyloxypyrimidine 3-oxide.
 5. Aprocess for the preparation of the2-amino-4-alkylamino-6-alkyloxypyrimidine 3-oxide compound of formula(I) as defined by claim 1, comprising reacting an aliphatic amine with2-amino-4,6-dichloropyrimidine in a solvent medium, next reacting thecompound thus obtained with a urea/H₂O₂ complex and phthalic anhydridein the presence of isopropanol, and thence reacting the compoundobtained with an excess of sodium alkoxide to provide the corresponding2-amino-4-alkylamino-6-alkyloxypyrimidine 3-oxide.